A systematic review of 64 randomized controlled trials (5299 participants) examined glutamate receptor modulators for unipolar major depression. Ketamine and esketamine may reduce depressive symptoms more than placebo within 24 hours, but the evidence for ketamine is very uncertain, while esketamine shows moderate-certainty evidence for increased remission. No difference in dropout rates was found between these drugs and placebo. Evidence for other glutamate modulators (memantine, lanicemine, etc.) is very limited. The authors call for long-term trials and real-world monitoring to establish safety and efficacy.
Intranasal esketamine plus an antidepressant reduced depression scores by about 3 points on the MADRS scale after 4 weeks, a statistically significant but small improvement that falls below the 6.5-point threshold for clinical significance used in the pivotal trials. A continuation trial showed reduced relapse risk, but a monotherapy trial had a larger effect with concerns about bias. Esketamine increased risks of sedation, dissociation, and other adverse events without increasing serious adverse events. No moderation by age or treatment resistance level was found. The clinical relevance of the benefit is unclear given the adverse event risks.